Increased differentiation of Th22 cells in Hashimoto^|^rsquo;s thyroiditis
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As Th22 subsets are identified, their involvement in the pathogenesis of numerous autoimmune diseases has become apparent. In this study, we investigated differentiation of Th22 cells in the autoimmune thyroid diseases including Hashimoto's thyroiditis (HT) and Graves' disease (GD). Besides, we also explored the involvement of Th22 cells in an iodine-induced autoimmune thyroiditis (AIT) model (i.e., NOD.H-2(h4) mice). In HT patients, we showed the level of circulating Th22 cells correlated with the level of serum IL-22, and was significantly higher than in GD patients and healthy control subjects. Levels of serum IL-6, a major Th22 cell differentiation effector, were also higher in HT, and correlated with Th22 cells concentration. Peripheral blood mononuclear cells isolated from HT patients produced larger amounts of IL-6 in vitro than did those isolated from other groups. Furthermore, unlike those from GD patients, T lymphocytes from HT patients showed an enhanced differentiation in vitro into Th22 cells in the presence of recombinant IL-6 and TNF-α. In addition, levels of circulating Th22 cells and titers of thyroid peroxidase antibody were positively correlated in HT patients. In NOD.H-2(h4) mice, higher numbers of Th22 cells were observed in the spleens of the AIT group, while splenocytes of this group also produced larger amounts of IL-6 and IL-22 in vitro compared with the control. Intra-thyroid infiltrating IL-22+ lymphocytes were significantly increased in mice of the AIT group compared with the control. Our results indicate that Th22 cells may contribute to the pathogenesis of HT.Keywords:
Autoimmune thyroiditis
Pathogenesis
Splenocyte
Interleukin 22
We have investigated the role of the spleen in the humoral and cellular immune response of rats with experimental autoimmune thyroiditis (EAT) induced by immunization with thyroglobulin and Freund's complete adjuvant. Animals subjected to splenectomy within 4 days of immunization developed lower thyroglobulin antibody levels and less severe thyroiditis compared to sham operated controls. There was no impairment in the ability of the animals to recover spontaneously from the disease after splenectomy. Together with the results obtained using splenocyte infusions, this suggests that suppressor cell production within the spleen plays only a small part in the normal immunological control which is presumably responsible for spontaneous regression of the disease.
Splenocyte
Thyroglobulin
Autoimmune thyroiditis
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To explore the relationship between IL-1β expression and two common autoimmune thyroid diseases: Hashimoto thyroiditis (HT) and Graves' disease (GD).qRT-PCR, Quantiglo ELISA, and flow cytometry were used to evaluate the expression levels of IL-1β in serum, peripheral blood mononuclear cells (PBMCs), and thyroid tissue samples from patients with HT or GD. Local infiltration of monocytes was assessed by immunohistochemical study of patients' thyroid tissue samples.Although no significant differences in IL-1β levels were found between samples of serum from patients with HT or GD and normal controls, we found that IL-1β mRNA and protein levels in PBMCs of HT patients were significantly higher than those of patients with GD, which were in turn higher than the level in normal controls. In addition, IL-1β mRNA was also increased in thyroid gland tissue from patients with HT compared to those with GD, and this was accompanied by increased local infiltration of monocytes into thyroid tissues. Correlation analysis of the clinical samples validated the association of high IL-1β levels with the pathogenesis of HT.Our study suggests that IL-1β may be an active etiologic factor in the pathogenesis of HT and thus present a new target for novel diagnostics and treatment.
Pathogenesis
Autoimmune thyroiditis
Thyroid disease
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The thyrocalcitonin content of the thyroid glands of euthyroid, hyperthyroid and hypothyroid rats fed a calcium deficient diet was determined in 2 separate experiments by bioassay. Hyperthyroidism was produced by the injection of 50 μg l-thyroxine or 200 mU thyrotropin per day, and hypothyroidism by the dietary administration of 0.05% propylthiouracil or an iodine deficient diet. The log-dose response curve for the hypocalcemic activity of the thyroid homogenates from the euthyroid rats was linear between 0.24 and 0.96 mg thyroid tissue, equivalent to 0.018–0.072 of a single rat thyroid gland. No significant differences in the hypocalcemic response of assay rats was observed when a comparison was made of thyroid tissue homogenates that included parathyroid tissue and thyroid homogenates in which the parathyroid gland was removed prior to tissue homogenization. Thyroxine consistently caused a significant 27–35% reduction in the thyroidal content of thyrocalcitonin, whereas the administration of thyrotropin caused a significant 33% reduction in only 1 of the 2 experiments. Hypothyroidism induced by propylthiouracil or a low iodide diet resulted in a slight increase in thyroidal content of thyrocalcitonin, which was significant in one experiment but no different from the control levels in the second experiment. The results obtained in the rats made hyperthyroid with thyroxine are probably due to an increased recycling of skeletal calcium secondary to the ability of thyroid hormone to accelerate bone resorption rather than a direct effect of thyroid hormone on the secretion of thyrocalcitonin. (Endocrinology81: 256, 1967)
Propylthiouracil
Wolff–Chaikoff effect
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Glucocorticoids are known regulators of thyroid function in vertebrates. In birds they have clear tissue-specific and age-dependent effects on thyroid hormone metabolism. In mammals, however, few studies exist addressing these aspects using an in vivo model system. We therefore set out to examine the acute effects of a single dose of dexamethasone (DEX) on plasma 3,5,3′-tri-iodothyronine (T 3 ) and thyroxine (T 4 ) levels, as well as on the activity of the different deiodinases in liver, kidney and brain in the developing rat. In 20-day-old fetuses (E20), glucocorticoids had no effects on circulating thyroid hormone levels despite their clear effects on hepatic and renal deiodinases, thereby indicating that under these conditions circulating thyroid hormone levels are more dependent on thyroidal secretion than on peripheral deiodination. In contrast, in 5-day-old rat pups, DEX did not seem to have any effects on hepatic and renal T 3 production (via the type I deiodinase), whereas type III deiodinase (D3) activity in both these tissues increased significantly. These observations therefore suggested that the DEX-induced increase in circulating T 3 levels is a direct consequence of the increase in plasma T 4 levels. In 12-day-old pups (P12), however, the main effect of glucocorticoids on circulating levels was by increasing inner ring deiodination T 3 through induction of D3 in both liver and kidney. Finally, in the brain, glucocorticoids stimulated thyroid hormone activity only during a short period of time (between E20 and P12) that largely overlaps with the transient window in time during which brain development is thyroid hormone sensitive. This was in contrast to the E20 and P12 brain, where the glucocorticoid-induced changes in type II deiodinase and D3 seemed to favor a status quo in local T 3 availability.
Iodothyronine deiodinase
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Placing rats soon after weaning on a low idoine diet and KClO4 resulted in hypothyroidism which was intense enough to produce effects similar to those following thyroid-ectomy on the plasma PBI, body growth and pituitary content of a protein associated with GH. Plasma insulin levels were also very low. Once growth stasis had occurred, l-T4 in very low doses (0.13−0.28 μg/100 g/day) or KI (1−11.5 μg I/day) was administered, while KClO4 treatment was continued until the animals were killed. These treatments were accompanied by an increase in the weight of the body and organs, the pituitary protein associated with GH, the plasma insulin levels, the plasma PBI, and sometimes the thyroidal 127I content. The weight of the thyroid gland increased significantly. The last of these effects was induced by exogenous insulin in the rats on low iodine diet + KClO4, although plasma TSH activity did not increase further. The results are discussed in relation to the hypothesis that a) the “goitrogenic” effects of small doses of thyroid hormones might be a consequence of partial restitution of the function of the pituitary and/or glands dependent on it, and b) full response of the thyroid to intense stimulation by TSH might require adequate levels of other hormones. (Endocrinology83: 41, 1968)
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Crystalline dihydrotachysterol (DHT) stimulates the activity of the thyroid gland in puberal female rats. After i.p. injection of 350 or 500 µ g/kg/day DHT, the height of epithelial thyroid cells increased, resulting in an increase of thyroid cells from 19 to 26% of the total follicle area. The secretory activity of the gland increased, serum TSH rising from 1.1 to 2.1 mU/ml and serum thyroxine rising from 2.5 to 6 µ g%. The basal metabolic rate increased from 1,400 to 1,810 ml O2/kg/h oxygen consumption. Body weight, however, did not differ from that of the control group. At a dosage of 750 µ g/kg/day, the above reaction was accompanied by a body weight drop of 20%. Within 4 h after implantation of crystalline DHT into the anterior basal hypothalamus, the thyroid reacted histologically with the above pattern of an active gland. These changes could not be elicited in hypophysectomized rats. These results would indicate that the stimulatory effect of DHT on the thyroid gland acts via the hypothalamo-pituitary axis.
Basal (medicine)
Hypothalamic–pituitary–thyroid axis
Endocrine gland
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Severe iodine deficiency is characterized by goiter, preferential synthesis, and secretion of T3 in thyroids, hypothyroxinemia in plasma and tissues, normal or low plasma T3, and slightly increased plasma TSH. We studied changes in deiodinase activities and mRNA in several tissues of rats maintained on low-iodine diets (LIDs) or LIDs supplemented with iodine (LID+I). T4 and T3 concentrations decreased in plasma, tissues, and thyroids of LID rats, and T4 decreased more than T3 (50%). The highest type 1 iodothyronine deiodinase (D1) activities were found in the thyroid, kidney, and the liver; pituitary, lung, and ovary had lower D1 activities; but the lowest levels were found in the heart and skeletal muscle. D1 activity decreased in all tissues of LID rats (10–40% of LID+I rats), except for ovary and thyroids, which D1 activity increased 2.5-fold. Maximal type 2 iodothyronine deiodinase (D2) activities were found in thyroid, brown adipose tissue, and pituitary, increasing 6.5-fold in thyroids of LID rats and about 20-fold in the whole gland. D2 always increased in response to LID, and maximal increases were found in the cerebral cortex (19-fold), thyroid, brown adipose tissue, and pituitary (6-fold). Lower D2 activities were found in the ovary, heart, and adrenal gland, which increased in LID. Type 3 iodothyronine deiodinase activity was undetectable. Thyroidal Dio1 and Dio2 mRNA increased in the LID rats, and Dio1 decreased in the lung, with no changes in mRNA expression in other tissues. Our data indicate that LID induces changes in deiodinase activities, especially in the thyroid, to counteract the low T4 synthesis and secretion, contributing to maintain the local T3 concentrations in the tissues with D2 activity.
Iodothyronine deiodinase
DIO2
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In an attempt to study the effect of adrenal steroids on plasma thyroid hormone concentration in patients with Hashimoto's thyroiditis, 2 mg dexamethasone was administered for 2–4 weeks to 9 patients with normal plasma TSH, 3 patients with compensatory increase of plasma TSH, and 10 patients with a marked elevation of plasma TSH. Dexamethasone depressed plasma T4, T3, and TSH and reduced thyroid size in nine euthyroid patients, whereas a similar treatment did not affect plasma T3 and T4, but reduced plasma TSH and thyroid size in three patients with compensatory increase of plasma TSH. In contrast, dexamethasone elevated plasma T3 and T4 in 10 hypothyroid patients with a marked elevation of plasma TSH. The increase of T3 was more than that of T4, suggesting preferential secretion of T3. Plasma TSH was reduced, but was still above normal after administration of dexamethasone. It is suggested that the intrathyroidal autoimmune processes inhibiting thyroid hormone synthesis are significant in patients with more severe Hashimoto's thyroiditis, and that dexamethasone stimulated hormone synthesis by depressing the autoimmune processes.
Autoimmune thyroiditis
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After the administration of estradiol benzoate (EB), testosterone propionate (TP) and progesterone (P)to Sprague-Dawley rats it was revealed that both the thyroid gland weight and the thyroxin-binding capacity of protein (TBCP) of the blood plasma were higher in the female than in the male animals. The female animals responsed to TP and P with lower values for total (TT4) and free thyrotoxin (T4)than the male animals. In the males EB elevated the level of TT4 and free T4, and in the females--the level of TT4 and TBCP. TP decreased the sensitivity of the thyroid gland to thyrotropic hormone. The stimulating effect of P on the thyroid gland resulted in its functional overstrain and exhaustion, which was stronger and more rapid in the female than in the male animals.
Testosterone propionate
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